Liver X receptor marks the spot

Multiple companies have shelved liver X receptor agonists for
cardiovascular indications because of unfavorable effects on lipid levels. Now,
a New York team and Rgenix Inc. have found a different
role for the agonists in metastatic melanoma.1

Those compounds hit both isotypes of LXR-LXR-b
(NR1H2) and LXR-α
(NR1H3)-as well as the related retinoid X receptor (RXR). The molecules raised
triglyceride levels in rodents and did not advance into clinical development.

Metastasis stasis

Tavazoie's team used tool compounds and a variety of cell
culture and mouse models to make the case for agonizing LXR-b to treat melanoma.

In vitro, nonselective LXR
agonists prevented invasion and endothelial recruitment, two key traits of
metastatic tumors. In several mouse models of melanoma, oral LXR agonists
prevented metastasis to the brain and lung and increased survival compared with
vehicle controls.

"When we fed mice with these drugs, we found that they
strongly suppressed melanoma growth and metastasis," said Tavazoie. "We
see 30-fold reductions in metastasis."

shRNA knockdown or antibody depletion of APOE blocked the
beneficial effects of LXR agonists, indicating that the treatment likely worked
by inducing the expression of APOE.

The team then used genetics to determine that somatic LXR-b was the key target for preventing melanoma
metastasis.

In Lxr-b
knockout mice, tumors did not respond to nonselective LXR agonists. Mice
lacking Lxr-a
responded comparably to wild-type mice with tumors. Thus, the team concluded
that activation of LXR-b but
not LXR-a in normal tissue
surrounding a tumor could combat metastasis.

Tavazoie thinks that raising APOE levels with LXR-b agonists is an attractive option for
melanomas as an adjunct to targeted therapies that directly block tumor cell
division.

Indeed, the team found that a combination of LXR agonists
with Zelboraf or a CTLA-4 antibody enhanced the drugs' effects on tumor
metastasis and increased survival in mice compared with Zelboraf or CTLA-4
antibody alone. The combination also worked in mice with tumors resistant to
Zelboraf.

"Zelboraf and Yervoy work in about half of patients,
but with our APOE activation therapy, there is response across all tumor types,
even tumors that have developed resistance to targeted therapies," said
Tavazoie, who is also cofounder and chair of the scientific advisory board at
Rgenix.

Results were reported in Cell and are covered by
pending patents licensed to Rgenix.

LXR revival

The challenge to using LXR agonists in melanoma is getting
selectivity for LXR-b while
avoiding cardiovascular liabilities.

Rgenix CEO David Darst said that the company in-licensed a
portfolio of patents late last year from an undisclosed pharma covering
composition of matter for a family of LXR agonists.

"Our lead candidate is chemically related to one of
the compounds used in the paper" but has undergone optimization to improve
its selectivity for LXR-b,
said Darst. "We're in the process of conducting a dose range-finding
toxicity study in monkeys."

Darst said that the company plans to be in the clinic by
the first half of 2015.

At least one other company-Vitae Pharmaceuticals Inc.-has
LXR-b-selective compounds in
development. Vitae's compounds are in preclinical testing for atherosclerosis
and atopic dermatitis. CSO Richard Gregg said that Vitae's LXR agonists are
highly selective for LXR-b
and thus have a more favorable effect on lipid levels than pan-LXR agonists.

"LXR has been around as a target for a long time,
about 10 years or so, but there have been certain problems of selectivity and
lipid elevation," said Gregg. "I don't believe there are many active
programs going on right now. People have largely dropped out of this space."

Tavazoie's study suggests that LXR agonists could "have
a very positive impact, inhibiting growth and metastasis" of melanoma,
said Gregg. "The downside is that LXR agonists have a tendency to induce
lipid synthesis, leading to increased circulating triglycerides and fat
accumulation in the liver."

"For atherosclerosis, this is a big downside, but for
tumors these side effects are better accepted," said Gregg. "If a
cancer is going to kill you in six months, elevated triglycerides are not as
much of a concern."

Tavazoie said that the lipid-altering effects of LXR
agonists are transient.

"Previous compounds have been shown to cause an acute
increase in levels of triglycerides, but this goes away," said Tavazoie. "This
should not be a concern for melanoma patients."

Rgenix was formed in 2010 to develop therapies for
metastatic cancer coming out of Tavazoie's lab. The company also has mAbs for
triple-negative breast cancer, including an antibody that targets insulin-like growth factor binding protein 2
(IGFBP2). Rgenix hopes to
partner its mAbs and is focused on internal development of its small molecules.

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